Isoergolines, for example, lisuride, are known to be effective agents for treatment of migraine. However, strong agonism of 5-HT1B receptor by migraine therapeutics such as, for example, sumatriptan (Phebus, Cephalalgia 17: 245 (1997)) and ergotamine frequently leads to adverse cardiovascular effects due to excessive vasoconstriction.
More recently, a number of highly selective agents for treatment of migraine which have high 5-HT1D:5-HT1B binding ratios have been prepared, such as, for example, the alkyltryptamine derivatives (125-fold selectivity, Slassi, Bioorg. Med. Chem. Lett. 10: 1707-1709, (2000)), the indole series (300-fold selectivity, Castro, J. Med. Chem. 41: 2667 (1998)) and the non-indole series (>6000-fold selectivity, Ennis, J. Med. Chem. 41: 2180 (1998), Armer et al., U.S. Patent Application No. 20140179705, Armer et al., U.S. Patent Application No. 20140179707). Accordingly, an effective migraine agent should be selective for the 5-HT1D receptor over the 5-HT1B receptor, but with moderate agonism of the 5-HT1B receptor to minimize non-cranial vasoconstriction. Antagonism of adrenergic receptors, such as, for example, alpha1A, alpha1D, alpha2A, alpha2B and alpha2C by migraine therapeutics can reduce vasoconstriction caused by strong 5-HT1B agonism.
Agonism of dopamine receptors is undesirable for anti-migraine compounds since nausea is a classic dopaminergic (activation of dopamine receptors) symptom, which is already an indication of migraine itself. Yet another problem with many migraine derivatives is undesirable agonism of 5-HT2B receptors which is associated with fibrosis, including cardiovascular valvulopathy (Rothman, Circulation 102: 2836 (2000)). Conversely, antagonism of 5-HT2B receptors may offer therapeutic advantages in the treatment and/or prevention of migraine (Schaerlinger, Br. J. Pharmacol. 140(2): 277-84, (2003)).
Accordingly, there is a continuing need for new compounds to treat and/or prevent disorders such as migraine, which selectively agonize 5-HT1D receptors while minimally agonizing 5-HT1B and dopamine receptors and are 5-HT2B and adrenergic receptor antagonists.